Expression of human apolipoprotein E reduces amyloid-β deposition in a mouse model of Alzheimer's disease

被引:282
作者
Holtzman, DM
Bales, KR
Wu, S
Bhat, P
Parsadanian, M
Fagan, AM
Chang, LK
Sun, YL
Paul, SM
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA
[4] Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA
关键词
D O I
10.1172/JCI6179
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
The epsilon 4 allele of apolipoprotein E (apo E) is associated with an increased risk for developing Alzheimer's disease (AD). This may be due to interactions between apo E and the amyloid-beta protein (A beta). To assess the effects of human apo E isoforms on A beta deposition in vivo, we bred apo E3 and apo E4 hemizygous (+/-) transgenic mice expressing apo E by astrocytes to mice homozygous (+/+) for a mutant amyloid precursor protein (APP(V717F)) transgene that develop age-dependent AD neuropathology. All mice were on a mouse apo E null (-/-) background. By nine months of age, APP(V717F-/-), apo E-/- mice had developed A beta deposition, and, as reported previously, the quantity of A beta deposits was significantly less than that seen in APP(V717F+/-) mice expressing mouse apo E. In contrast to effects of mouse apo E, similar levels of human apo E3 and apo E4 markedly suppressed early A beta deposition at nine months of age in APP(V717F-/-) transgenic mice, even when compared with mice lacking apo E. These findings suggest that human apo E isoforms decrease A beta aggregation or increase A beta clearance relative to an environment in which mouse apo E or no apo E is present. The results may have important implications for understanding mechanisms underlying the link between apo E and AD.
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页码:R15 / R21
页数:7
相关论文
共 60 条
  • [1] Bales K. R., 1998, Society for Neuroscience Abstracts, V24, P1502
  • [2] Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition
    Bales, KR
    Verina, T
    Dodel, RC
    Du, YS
    Altstiel, L
    Bender, M
    Hyslop, P
    Johnstone, EM
    Little, SP
    Cummins, DJ
    Piccardo, P
    Ghetti, B
    Paul, SM
    [J]. NATURE GENETICS, 1997, 17 (03) : 263 - 264
  • [3] MACROPHAGE-SPECIFIC EXPRESSION OF HUMAN APOLIPOPROTEIN-E REDUCES ATHEROSCLEROSIS IN HYPERCHOLESTEROLEMIC APOLIPOPROTEIN E-NULL MICE
    BELLOSTA, S
    MAHLEY, RW
    SANAN, DA
    MURATA, J
    NEWLAND, DL
    TAYLOR, JM
    PITAS, RE
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (05) : 2170 - 2179
  • [4] Co-expression of beta-amyloid precursor protein (beta APP) and apolipoprotein E in cell culture: Analysis of beta APP processing
    Biere, AL
    Ostaszewski, B
    Zhao, HW
    Gillespie, S
    Younkin, SG
    Selkoe, DJ
    [J]. NEUROBIOLOGY OF DISEASE, 1995, 2 (03) : 177 - 187
  • [5] Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma
    Biere, AL
    Ostaszewski, B
    Stimson, ER
    Hyman, BT
    Maggio, JE
    Selkoe, DJ
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (51) : 32916 - 32922
  • [6] Alpha-2 macroglobulin is genetically associated with Alzheimer disease
    Blacker, D
    Wilcox, MA
    Laird, NM
    Rodes, L
    Horvath, SM
    Go, RCP
    Perry, R
    Watson, B
    Bassett, SS
    McInnis, MG
    Albert, MS
    Hyman, BT
    Tanzi, RE
    [J]. NATURE GENETICS, 1998, 19 (04) : 357 - 360
  • [7] APOLIPOPROTEIN-E ASSOCIATED WITH ASTROCYTIC GLIA OF THE CENTRAL NERVOUS-SYSTEM AND WITH NONMYELINATING GLIA OF THE PERIPHERAL NERVOUS-SYSTEM
    BOYLES, JK
    PITAS, RE
    WILSON, E
    MAHLEY, RW
    TAYLOR, JM
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1985, 76 (04) : 1501 - 1513
  • [8] FIBRILLOGENESIS IN ALZHEIMERS-DISEASE OF AMYLOID-BETA PEPTIDES AND APOLIPOPROTEIN-E
    CASTANO, EM
    PRELLI, F
    WISNIEWSKI, T
    GOLABEK, A
    KUMAR, RA
    SOTO, C
    FRANGIONE, B
    [J]. BIOCHEMICAL JOURNAL, 1995, 306 : 599 - 604
  • [9] Cavalieri, 1966, GEOMETRIA INDIVISIBI
  • [10] Expression of the very low-density lipoprotein receptor (VLDL-r), an apolipoprotein-E receptor, in the central nervous system and in Alzheimer's disease
    Christie, RH
    Chung, H
    Rebeck, GW
    Strickland, D
    Hyman, BT
    [J]. JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 1996, 55 (04) : 491 - 498